期刊
NATURE COMMUNICATIONS
卷 9, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-018-07698-6
关键词
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资金
- Futuro e Ricerca 2010 [RBFR10HP97_004]
- Fondo per lo Sviluppo e la Coesione 2007-2013-Regione Piemonte [A11_2015_12C]
- Regione Piemonte Bando regionale a sostegno di progetti di ricerca industriale e/o sviluppo sperimentale sulle malattie autoimmuni e allergiche (PARFSC 2007/2013
- TIPSO project)
- AIRC [16813]
- Compagnia di SanPaolo [CSTO161109]
- Conselho Nacional de Desenvolvimento Cientifico e Tecnologico-CNPq/Brazil [474887/2011-1-Edital Universal 14/2011]
- Fundacao de Amparo a Pesquisa do Estado de Minas Gerais-FAPEMIG/Brazil [CBB APQ-03570-16-Edital Universal 01/2016]
- Pro-Reitoria de Pesquisa da Universidade Federal de Minas Gerais, Brazil
- Capes [88887.115812/2016-00, 88881.119732/2016-01]
- FIRC fellowship
- PRONEX/FUNCAP/CNPq [PR2-0101-00054.01.00/15]
PI3K activation plays a central role in the development of pulmonary inflammation and tissue remodeling. PI3K inhibitors may thus offer an improved therapeutic opportunity to treat non-resolving lung inflammation but their action is limited by unwanted on-target systemic toxicity. Here we present CL27c, a prodrug pan-PI3K inhibitor designed for local therapy, and investigate whether inhaled CL27c is effective in asthma and pulmonary fibrosis. Mice inhaling CL27c show reduced insulin-evoked Akt phosphorylation in lungs, but no change in other tissues and no increase in blood glycaemia, in line with a local action. In murine models of acute or glucocorticoid-resistant neutrophilic asthma, inhaled CL27c reduces inflammation and improves lung function. Finally, inhaled CL27c administered in a therapeutic setting protects from bleomycin-induced lung fibrosis, ultimately leading to significantly improved survival. Therefore, local delivery of a pan-PI3K inhibitor prodrug reduces systemic on-target side effects but effectively treats asthma and irreversible pulmonary fibrosis.
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